Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to death on average in 3 years (1). There is no cure or known treatment that significantly improves function. Loss of motor neurons in the brain and spinal cord of ALS patients causes the progressive symptoms. Motor nerve degeneration may result from a cascade of events including free radical toxicity, glutamate excitotoxicity and mitochondrial dysfunction (2-4), which lead to the activation of cell death pathways (5-9). Mitogen activated protein (MAP) kinases, including p38, are up-regulated in response to cell stress, and promote pro-apoptotic and inflammatory mediators (10, 11 ). Caspase enzymes and inflammatory mediators regulate cell death pathways (12-14) and are activated in human and transgenic mouse-model ALS (15,16). Caspase enzyme inhibitors and anti-inflammatory agents have been shown to slow progression in the ALS model (6,7,17,18). Minocycline, FDA approved for treatment of infection, has high central nervous system penetration when taken orally, inhibits p38 MAP kinase, prevents activation of caspase-1, caspase-3 and inflammatory mediators (19,20), and delays disease progression in animal models of neurodegenerative disorders, including Huntington disease (19), Parkinson disease (21) and ALS (22) (Serge Przedborski, personal communication). It is well tolerated as an oral treatment for outpatients. The objective of this clinical trial is to determine whether minocycline slows disease progression and helps maintain function in patients with ALS. The study design selects patients early in the course of ALS when a neuroprotective therapy may be most beneficial, measures functional improvement from the medication, which patients and physicians consider most important, and minimizes subject drop out. The proposed study will be an IRB-approved, investigator-initiated, multi-center, randomized, double blind, placebo-controlled study of minocycline in 400 subjects with ALS treated for 9 months. The primary outcome measure is the change in slope of the revised ALS Functional Rating Scale (ALSFRS-R). Secondary outcome measures consist of changes in disease progression rate as measured by manual muscle testing (MMT), forced vital capacity (percent predicted) and survival. Should minocycline prove effective in slowing the rate of functional decline, it would have an immediate impact both clinically and from the perspective of understanding the underlying pathophysiology of human ALS. This application is the clinical part of a combined proposal to carry out the clinical trial. A Data Center will be established at the California Pacific Medical Center in San Francisco to carry out data management and statistical analyses (see companion grant application Phase III Trial of Minocycline in ALS: II Data Center. P.I. Dr. Robert Miller).